Chaste — Cancer, Heart And Soft Tissue Environment — is an open source C++ library for the computational simulation of mathematical models developed for physiology and biology. Code development has been driven by two initial applications: cardiac electrophysiology and cancer development. A large number of cardiac electrophysiology studies have been enabled and performed, including high-performance computational investigations of defibrillation on realistic human cardiac geometries. New models for the initiation and growth of tumours have been developed. In particular, cell-based simulations have provided novel insight into the role of stem cells in the colorectal crypt. Chaste is constantly evolving and is now being applied to a far wider range of problems. The code provides modules for handling common scientific computing components, such as meshes and solvers for ordinary and partial differential equations (ODEs/PDEs). Re-use of these components avoids the need for researchers to ‘re-invent the wheel’ with each new project, accelerating the rate of progress in new applications. Chaste is developed using industrially-derived techniques, in particular test-driven development, to ensure code quality, re-use and reliability. In this article we provide examples that illustrate the types of problems Chaste can be used to solve, which can be run on a desktop computer. We highlight some scientific studies that have used or are using Chaste, and the insights they have provided. The source code, both for specific releases and the development version, is available to download under an open source Berkeley Software Distribution (BSD) licence at http://www.cs.ox.ac.uk/chaste, together with details of a mailing list and links to documentation and tutorials.

Enhanced temporal and spatial variability in cardiac repolarization has been related to increased arrhythmic risk both clinically and experimentally. Causes and modulators of variability in repolarization and their implications in arrhythmogenesis are however not well understood. At the ionic level, the slow component of the delayed rectifier potassium current (I(Ks)) is an important determinant of ventricular repolarization. In this study, a combination of experimental and computational multiscale studies is used to investigate the role of intrinsic and extrinsic noise in I(Ks) in modulating temporal and spatial variability in ventricular repolarization in human and guinea pig. Results show that under physiological conditions: i), stochastic fluctuations in I(Ks) gating properties (i.e., intrinsic noise) cause significant beat-to-beat variability in action potential duration (APD) in isolated cells, whereas cell-to-cell differences in channel numbers (i.e., extrinsic noise) also contribute to cell-to-cell APD differences; ii), in tissue, electrotonic interactions mask the effect of I(Ks) noise, resulting in a significant decrease in APD temporal and spatial variability compared to isolated cells. Pathological conditions resulting in gap junctional uncoupling or a decrease in repolarization reserve uncover the manifestation of I(Ks) noise at cellular and tissue level, resulting in enhanced ventricular variability and abnormalities in repolarization such as afterdepolarizations and alternans.

Interstitial cells of Cajal (ICC) are responsible for the spontaneous and omnipresent electrical activity in the stomach. A quantitative description of the intracellular processes whose coordinated activity is believed to generate electrical slow waves has been developed and is presented here. In line with recent experimental evidence, the model describes how the interplay between the mitochondria and the endoplasmic reticulum in cycling intracellular Ca(2+) provides the primary regulatory signal for the initiation of the slow wave. The major ion channels that have been identified as influencing slow wave activity have been modeled according to data obtained from isolated ICC. The model has been validated by comparing the simulated profile of the slow waves with experimental recordings and shows good correspondence in terms of frequency, amplitude, and shape in both control and pharmacologically altered conditions.

A physiologically realistic quantitative description of the electrical behavior of a gastric smooth muscle (SM) cell is presented. The model describes the response of a SM cell when activated by an electrical stimulus coming from the network of interstitial cells of Cajal (ICC) and is mediated by the activation of different ion channels species in the plasma membrane. The conductances (predominantly Ca2+ and K+) that are believed to substantially contribute to the membrane potential fluctuations during slow wave activity have been included in the model. A phenomenological description of intracellular Ca2+ dynamics has also been included because of its primary importance in regulating a number of cellular processes. In terms of shape, duration, and amplitude, the resulting simulated smooth muscle depolarizations (SMDs) are in good agreement with experimentally recordings from mammalian gastric SM in control and altered conditions. This model has also been designed to be suitable for incorporation into large scale multicellular simulations.

Corrias A, Giles W, Rodriguez B. Ionic mechanisms of electrophysiological properties and repolarization abnormalities in rabbit Purkinje fibers. Am J Physiol Heart Circ Physiol 300: H1806-H1813, 2011. First published February 18, 2011 doi:10.1152/ajpheart.01170.2010.-Purkinje cells play an important role in drug-induced arrhythmogenesis and are widely used in preclinical drug safety assessments. Repolarization abnormalities such as action potential (AP) prolongation and early afterdeploarizations (EAD) are often observed in vitro upon pharmacological interventions. However, because drugs do not act on only one defined target, it is often difficult to fully explain the mechanisms of action and their potential arrhythmogenicity. Computational models, when appropriately detailed and validated, can be used to gain mechanistic insights into the mechanisms of action of certain drugs. Nevertheless, no model of Purkinje electrophysiology that is able to reproduce characteristic Purkinje responses to drug-induced changes in ionic current conductances such as AP prolongation and EAD generation currently exists. In this study, a novel biophysically detailed model of rabbit Purkinje electrophysiology was developed by integration of data from voltage-clamp and AP experimental recordings. Upon validation, we demonstrate that the model reproduces many key electrophysiological properties of rabbit Purkinje cells. These include: AP morphology and duration, both input resistance and rate dependence properties as well as response to hyperkalemia. Pharmacological interventions such as inward rectifier K ϩ current and rapid delayed rectifier K ϩ current block as well as late Na ϩ current increase result in significant AP changes. However, enhanced L-type Ca 2ϩ current (iCaL) dominates in EAD genesis in Purkinje fibers. In addition, iCaL inactivation dynamics and intercellular coupling in tissue strongly modulate EAD formation. We conclude that EAD generation in Purkinje cells is mediated by an increase in iCaL and modulated by its inactivation kinetics. electrophysiology; Purkinje; early afterdepolarization; arrhythmia FOR DECADES, PURKINJE FIBERS have been implicated in the initiation of lethal cardiac arrhythmias such as ventricular fibrillation and Torsades de Pointes in a variety of clinical situations. In patients with congenital long QT syndrome or Brugada syndrome, for example, the Purkinje-myocardial interface is often the location where ventricular fibrillation initiated (15). Adverse side effects of drugs belonging to a broad range of categories are important factors that have long been associated with arrhythmogenesis. Regulatory agencies have identified Purkinje fibers as an important tool in preclinical assessment of drug safety. Both the Food and Drug Administration and the European Medicines Agency recommend the Purkinje fiber assay for in vitro electrophysiological studies as valuable for assessing potential arrhythmogenicity of a tested compound (41). Aubert et al. (2) have specifically evaluated the rabbit Purkinj...

Interstitial cells of Cajal (ICC) isolated from different regions of the stomach generate spontaneous electrical slow wave activity at different frequencies, with cells from the proximal stomach pacing faster than their distal counterparts. However, in vivo there exists a uniform pacing frequency; slow waves propagate aborally from the proximal stomach and subsequently entrain distal tissues. Significant resting membrane potential (RMP) gradients also exist within the stomach whereby membrane polarization generally increases from the fundus to the antrum. Both of these factors play a major role in the macroscopic electrical behavior of the stomach and as such, any tissue or organ level model of gastric electrophysiology should ensure that these phenomena are properly described. This study details a dual-cable model of gastric electrical activity that incorporates biophysically detailed single-cell models of the two predominant cell types, the ICC and smooth muscle cells. Mechanisms for the entrainment of the intrinsic pacing frequency gradient and for the establishment of the RMP gradient are presented. The resulting construct is able to reproduce experimentally recorded slow wave activity and provides a platform on which our understanding of gastric electrical activity can advance.

Pharmacological treatment of atrial fibrillation (AF) exhibits limited efficacy. Further developments require a comprehensive characterization of ionic modulators of electrophysiology in human atria. Our aim is to systematically investigate the relative importance of ionic properties in modulating excitability, refractoriness, and rotor dynamics in human atria before and after AF-related electrical remodeling (AFER). Computer simulations of single cell and tissue atrial electrophysiology were conducted using two human atrial action potential (AP) models. Changes in AP, refractory period (RP), conduction velocity (CV), and rotor dynamics caused by alterations in key properties of all atrial ionic currents were characterized before and after AFER. Results show that the investigated human atrial electrophysiological properties are primarily modulated by maximal value of Na+/K+ pump current ( GNaK) as well as conductances of inward rectifier potassium current ( GK1) and fast inward sodium current ( GNa). GNaK plays a fundamental role through both electrogenic and homeostatic modulation of AP duration (APD), APD restitution, RP, and reentrant dominant frequency (DF). GK1 controls DF through modulation of AP, APD restitution, RP, and CV. GNa is key in determining DF through alteration of CV and RP, particularly in AFER. Changes in ionic currents have qualitatively similar effects in control and AFER, but effects are smaller in AFER. The systematic analysis conducted in this study unravels the important role of the Na+/K+ pump current in determining human atrial electrophysiology.

In this paper, we illustrate how advanced computational modelling and simulation can be used to investigate drug-induced effects on cardiac electrophysiology and on specific biomarkers of pro-arrhythmic risk. To do so, we first perform a thorough literature review of proposed arrhythmic risk biomarkers from the ionic to the electrocardiogram levels. The review highlights the variety of proposed biomarkers, the complexity of the mechanisms of drug-induced pro-arrhythmia and the existence of significant animal species differences in drug-induced effects on cardiac electrophysiology. Predicting drug-induced pro-arrhythmic risk solely using experiments is challenging both preclinically and clinically, as attested by the rise in the cost of releasing new compounds to the market. Computational modelling and simulation has significantly contributed to the understanding of cardiac electrophysiology and arrhythmias over the last 40 years. In the second part of this paper, we illustrate how state-of-the-art open source computational modelling and simulation tools can be used to simulate multi-scale effects of drug-induced ion channel block in ventricular electrophysiology at the cellular, tissue and whole ventricular levels for different animal species. We believe that the use of computational modelling and simulation in combination with experimental techniques could be a powerful tool for the assessment of drug safety pharmacology.